Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes

Abstract

Introduction: This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.

Methods: Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.

Results: Canagliflozin increased UGE dose-dependently (∼80-120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.

Conclusions: Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00963768.

Conflict of interest statement

Competing Interests: The authors have the following interests. This study was sponsored by Janssen Research & Development, LLC. Editorial support was provided by Cherie Koch, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. The funding organization was involved in the design, data collection and analysis, and preparation of the manuscript for publication. Sue Sha, Damayanthi Devineni, Atalanta Ghosh, David Polidori, Keith Demarest and Paul Rothenberg are employed by Janssen Research & Development. Marcus Hompesch and Linda Morrow are employed by Profil Institute for Clinical Research and Sabine Arnolds and Heike Spitzer by Profil Institut für Stoffwechselforschung GmbH. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Study flow diagram.

PBO, placebo; QD, once daily; CANA, canagliflozin; BID, twice daily. *Safety analysis set.

Figure 2. Change from baseline in 24-hour UGE.

UGE, urinary glucose excretion; PBO, placebo; CANA, canagliflozin; QD, once daily; BID, twice daily.

Figure 3. Relationship between baseline 24-hour mean RTG and 24-hour mean PG.

(A) Distribution of 24-hour mean RTG values at baseline and (B) correlation between RTG and 24-hour mean PG prior to canagliflozin treatment. RTG, renal threshold for glucose; PG, plasma glucose.

Figure 4. Change in RTG by total daily dose of canagliflozin (Day 16).

* RTG, renal threshold for glucose; BID, twice daily. *Data are from Western patients only. †Canagliflozin 300 mg BID.

Figure 5. Mean (A) PG and (B) plasma insulin levels before (Day –1) and after a single dose (Day 1) and after multiple doses (Day 16) of canagliflozin 100 mg QD.

PG, plasma glucose; QD, once daily.

Figure 6. Mean change in body weight with daily canagliflozin treatment.

PBO, placebo; CANA, canagliflozin; QD, once daily; BID, twice daily.

Figure 7. Mean 24-hour urine volume at baseline (Day –1) and after a single dose (Day 1) and after multiple doses (Day 16).

SD, standard deviation; PBO, placebo; CANA, canagliflozin; QD, once daily; BID, twice daily.